tbuckley/cabot-search huggingface dataset:
Efficacy and safety of recombinant human endostatin combined with whole-brain radiotherapy in patients with brain metastases from NSCLC.
Authors: Lingjuan Chen, Fan Tong, Ling Peng, Yu Huang, Ping Yin, Yue Feng, Shishi Cheng, Jing Wang, Xiaorong Dong
Journal: Journal of Clinical Oncology (2022)

e21158 Background: Brain metastasis (BM) is the first cause of poor prognosis in non-small cell lung cancer (NSCLC) patients. To date, localized whole-brain radiotherapy (WBRT) is still the therapeutic option for patients with extensive BM. However, effectiveness is currently unsatisfactory. This study aimed to investigate the effects of Rh-endostatin combined with WBRT on NSCLC patients with BMs. Methods: 43 NSCLC patients with BMs were divided into two groups randomly. Rh-endostatin combination group (n = 19) received WBRT combined with Rh-endostatin, and radiation group (n = 24) received WBRT alone. The primary endpoint of the study was progression free survival (PFS). The secondary endpoints were intracranial progression free survival (iPFS), overall survival (OS), objective response rate (ORR) and the change of cerebral blood volume (CBV), cerebral blood flow (CBF) of the contrast medium pre- and one month post-radiation. Results: Median progression-free survival (PFS) was 8.1 months in the Rh-endostatin combination group versus 4.9 months in the radiation group (95%CI: 0.2612-0.9583, p= 0·0428). Besides, median iPFS was 11.6 months in Rh-endostatin combination group versus 4.8 months in the radiation group (95%CI：0.2530-0.9504, p= 0·0437). Overall survival (OS) was 14.2 months in the Rh-endostatin combination group versus 6.4 months in the radiation group (95%CI：0.2508-1.026, p= 0·0688). Compared with radiotherapy alone, CBV and CBF in the Rh-endostatin combination group increased more significantly than before radiotherapy, indicating that Rh-endostatin may improve local blood supply and microcirculation. Conclusions: Rh-endostatin showed better survival and a safety profile, improved cerebral perfusion and increased the quality of life of NSCLC patients with BMs. Clinical trial information: NCT03614065.
NFB-09. Treatment of cardiac fibroma in a<i>PTCH1</i>-mutated Gorlin syndrome with medulloblastoma
Authors: Gianluca Piccolo, Antonio Verrico, Gianluca Trocchio, Maria Derchi, Alessandra Siboldi, Nicola Stagnaro, Marco Crocco, Angela Di Giannatale, Paola Ghiorzo, Claudia Milanaccio, Maria Luisa Garrè
Journal: Neuro-Oncology (2022)

Abstract A 2,5-year-old girl presented vomiting episodes associated with severe motor delay, macrocephaly, and distal hypotonia. Brain MRI showed hydrocephalus and a non-metastatic lesion in the posterior fossa. A pre-operative ECG showed isodifasic T waves in leads V4R and V1, follow-up was recommended. Histology after gross total resection was consistent with Desmoplastic/Nodular Medulloblastoma. At chest X-rays a bifid rib was noted, leading to the diagnosis of Gorlin syndrome (GS; c.3306 + 1G&amp;gt;T in PTCH1). During chemotherapy, ventricular tachycardia (VT) occurred, requiring synchronized electrical cardioversion. An echocardiogram revealed an echogenic mass of the left ventricle free wall, but normal coronaries and ventricular function. Cardiac MRI (CMR) confirmed a 21x40x38mm mass, with eccentric development and intense homogeneous enhancement, indicative of cardiac fibroma (CF). A computed tomography excluded local calcifications. Therapy with amiodarone and beta-blocker was initiated. TREATMENT STRATEGY: priority to chemotherapy vs cardiac surgery; full-dose chemotherapy, preferring drugs with minor cardiotoxicity; administration in ICU under continuous vital parameters and ECG-monitoring. Other three VTs occurred during treatment or anesthesia, resolved after electrical cardioversion (unsuccessful attempts with i.v. adenosine and amiodarone). Lacking specific guidelines concerning CF in GS, a wait-and-see approach was preferred with close tumor follow-up and regular cardiological assessment (ECG, stress-test, Holter monitoring, CMR). No further arrhythmias were recorded in a 10-year-long follow-up and CMR confirmed CF stability. Medulloblastoma has never recurred. PTCH1 variants are rarely associated with medulloblastoma (&amp;lt;2%). Only 3–5% of GS present CF, responsible for arrhythmias in 32%. Being non-regressing, total surgical resection is usually performed (without recurrence), with a 27-year-long median survival. When surgery risk/benefit ratio is not favorable or the patient is paucisymptomatic, the treatment plan remains unclear; probably, a conservative approach under a strict cardiological follow-up can be reasonable. In young children with syndromic medulloblastoma, a routine echocardiogram should be performed to rule out CF.
TALAPRO-3: A phase 3, double-blind, randomized study of enzalutamide (ENZA) plus talazoparib (TALA) versus placebo plus ENZA in patients with DDR gene–mutated, metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Neeraj Agarwal, Fred Saad, Arun Azad, Joaquin Mateo, Nobuaki Matsubara, Neal D. Shore, Jayeta Chakrabarti, Hsiang-Chun Chen, Silvana Lanzalone, Alexander Niyazov, Karim Fizazi
Journal: Journal of Clinical Oncology (2022)

TPS5096 Background: TALA is a poly(ADP-ribose) polymerase inhibitor (PARPi) approved as monotherapy for germline BRCA1/2-mutated HER2-negative advanced breast cancer. Clinical efficacy in metastatic castration-resistant prostate cancers (mCRPC) with alterations in DNA damage response (DDR) genes involved directly or indirectly in homologous recombination repair (HRR) has been demonstrated with some PARPi. Phase 3 study findings (de Bono et al. N Engl J Med, 2020;382:2091-2102) resulted in the approval of olaparib for mCRPC. ENZA is an androgen receptor (AR) inhibitor and established therapy for mCSPC. Since PARP activity has been shown to support AR function, PARP inhibition may increase sensitivity to AR-directed therapies. In addition, AR blockade downregulates HRR gene regulation, which has been hypothesized to induce a “ BRCAness” phenotype. A Phase 2 study of TALA monotherapy (TALAPRO-1) demonstrated robust antitumor activity in men with heavily pretreated, HRR-mutated mCRPC. The Phase 3, double-blind, randomized trial TALAPRO-3 (NCT04821622) herein presented will compare the combination of TALA plus ENZA vs placebo plus ENZA in men with mCSPC with DDR/HRR alterations. Methods: Approximately 550 patients with mCSPC harboring DDR/HRR alterations will be randomized to TALA (0.5 mg once daily) plus ENZA (160 mg once daily) or placebo (once daily) plus ENZA (160 mg once daily). Patients will be stratified according to de novo mCSPC vs relapsed mCSPC, high-volume disease vs low-volume disease, where high-volume disease is defined as the presence of visceral metastases or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis and BRCA vs non-BRCA mutational status. Key eligibility criteria include age ≥18 years; histological diagnosis of prostate cancer; alterations in at least one of 12 DDR/HRR genes known to sensitize patients to PARPi ( ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C); and metastatic disease (no brain metastases). Primary endpoint is rPFS (time to radiographic progression in soft tissue per RECIST 1.1 or in bone per PCWG3 criteria by investigator, or death). Secondary endpoints include overall survival, safety, and patient-reported outcomes. Patient recruitment is planned at approximately 285 sites in 27 countries, including the US and Europe, South America, South Africa, and Asia-Pacific. This study was approved by an Institutional Review Board. Clinical trial information: NCT04821622.
Rgs16 promotes antitumor CD8 <sup>+</sup> T cell exhaustion
Authors: Nina Weisshaar, Jingxia Wu, Yanan Ming, Alaa Madi, Agnes Hotz-Wagenblatt, Sicong Ma, Alessa Mieg, Marvin Hering, Ferdinand Zettl, Kerstin Mohr, Tilo Schlimbach, Nora Ten Bosch, Franziska Hertel, Lisann Müller, Hannah Byren, Mona Wang, Helena Borgers, Mareike Munz, Lukas Schmitt, Franciscus van der Hoeven, Ulrich Kloz, Rafael Carretero, Nikolai Schleußner, Rene-Filip Jackstadt, Ilse Hofmann, Guoliang Cui
Journal: Science Immunology (2022)

T cells become functionally exhausted in tumors, limiting T cell-based immunotherapies. Although several transcription factors regulating the exhausted T (Tex) cell differentiation are known, comparatively little is known about the regulators of Tex cell survival. Here, we reported that the regulator of G protein signaling 16 (Rgs-16) suppressed Tex cell survival in tumors. By performing lineage tracing using reporter mice in which mCherry marked Rgs16-expressing cells, we identified that Rgs16+CD8+ tumor-infiltrating lymphocytes (TILs) were terminally differentiated, expressed low levels of T cell factor 1 (Tcf1), and underwent apoptosis as early as 6 days after the onset of Rgs16 expression. Rgs16 deficiency inhibited CD8+ T cell apoptosis and promoted antitumor effector functions of CD8+ T cells. Furthermore, Rgs16 deficiency synergized with programmed cell death protein 1 (PD-1) blockade to enhance antitumor CD8+ T cell responses. Proteomics revealed that Rgs16 interacted with the scaffold protein IQGAP1, suppressed the recruitment of Ras and B-Raf, and inhibited Erk1 activation. Rgs16 deficiency enhanced antitumor CD8+ TIL survival in an Erk1-dependent manner. Loss of function of Erk1 decreased antitumor functions of Rgs16-deficient CD8+ T cells. RGS16 mRNA expression levels in CD8+ TILs of patients with melanoma negatively correlated with genes associated with T cell stemness, such as SELL, TCF7, and IL7R, and predicted low responses to PD-1 blockade. This study uncovers Rgs16 as an inhibitor of Tex cell survival in tumors and has implications for improving T cell-based immunotherapies.
Propensity-score analysis comparing perioperative and functional outcomes between XPS 180 W-photovaporization and GreenLight laser enucleation of the prostate: Reasons to discard vaporization and move to enucleation
Authors: A. Gasmi, Z-E. Khene, S. Guérin, K. Bensalah, B. Peyronnet, R. Mathieu, M. Roupret, R. Enrique, B. Pradère, V. Misrai
Journal: European Urology (2022)
<i>TSC1</i>-mutant bladder cancer expression signature in relation to nuclear localization of TFE3 and potential for targetable dependency.
Authors: Clemens Kemena Probst, Elio Adib, Magdalena Losko, Heng Du, Michelle S. Hirsch, Krinio Giannikou, David J. Kwiatkowski
Journal: Journal of Clinical Oncology (2022)

e16532 Background: Mutation and inactivation of the tumor suppressor gene TSC1 is a recurrent (6-10%) event in bladder cancer, but whether it functions as a driver event for tumor development has been uncertain. Methods: We performed differential gene expression and pathway analyses using RNA-seq data from the curated TCGA TSC1 mutant BLCA (n = 26) and TSC1 wild-type BLCA (n = 382) cohort and compared to an internal cohort of putative TSC1/TSC2-driven tumors (n = 63). Mechanistic studies, as well as RNA-seq and H3K27ac ChIP-seq analyses, were conducted in 2 TSC1 mutant/WT BLCA cell lines. Results: Comparison of The Cancer Genome Atlas (TCGA) TSC1-mutant bladder cancers ( TSC1mBLCA) with TCGA TSC1 wildtype tumors ( TSC1WTBLCA) identified a conserved TSC-associated expression signature, similar to ones seen in syndromic TSC tumors. GSEA and DESeq2 analyses implicated both mTORC1 hyperactivation, as well as activation of lysosomal pathways in TSC1mBLCA. We validated our findings by IHC analysis of a separate cohort of TSC1mBLCA (n = 5), compared to TSC1WTBLCA (n = 5). In addition, we found that TFE3, a transcriptional regulator of lysosomal gene expression, was relatively highly expressed in BLCA (compared to other MiT-TFE genes) and was localized to the nucleus in TSC1mBLCA but not in TSC1WTBLCA. Mechanistic studies of two TSC1mBLCA cell lines and their respective TSC1 addback derivatives, recapitulated the phenotype found in human tumors and demonstrated that TFE3 was both post-translationally modified and predominantly nuclear in TSC1-null cell lines compared to TSC1 addbacks. RNA-seq and H3K27ac ChIP-Seq analyses showed that TSC1mBLCA cell lines retained elements of the TSC-associated expression signature that was seen in TSC1mBLCA tumors, confirming differential activation of TFE3 in response to TSC1 loss. Nuclear localization of TFE3 in TSC1mBLCA cell lines was only partially reversed by rapamycin treatment and was unaffected by treatment of Torin1. SiRNA mediated knockdown of TFE3 significantly decreased cell growth and viability in TSC1mBLCA cell lines and did not result in compensatory upregulation of TFEB and MITF. Conclusions: Our findings indicate that TSC1 mutant bladder tumors retain elements of a conserved transcriptional signature that is characterized by nuclear localization and activation of TFE3. Aberrant TFE3 activation likely contributes to TSC1mBLCA development and may therefore be amenable to targeted therapy.
Association between tumor mutational burden (TMB) and mutational profile and its effect on overall survival: A post hoc analysis of patients with TMB-high and TMB-low metastatic cancer treated with immune checkpoint inhibitors (ICI).
Authors: Camila Bragança Xavier, Gabriela Guardia, Carlos Diego Holanda Lopes, Beatriz Mendes Awni, Eduardo Felicio Campos, João Pedro Alves, Anamaria Aranha Camargo, Pedro Alexandre Favoretto Galante, Denis L. Jardim
Journal: Journal of Clinical Oncology (2022)

2632 Background: High-TMB was recently approved as an agnostic biomarker for pembrolizumab in advanced cancers. Still, several patients with high-TMB do not respond to ICI, while some patients with low-TMB benefit from immunotherapy. Methods: We collected genomic (MSK-IMPACTassay) and survival data from 1,661 patients and assessed OS (Kaplan-Meier method) according to the mutational status. To better qualify patients with TMB ≥ 10 mut/Mb (TMB-H) (N = 488, 29%) and TMB &lt; 10 mut/Mb (TMB-L) (N = 1,173, 71%) for ICI treatment, we analyzed single gene alterations impacting OS (P &lt; 0.05). For all genes exhibiting a correlation with OS, we conducted a Cox multivariate analysis stratified by median TMB, sex, median age, microsatellite instability (MSI) status, and histology. Results: Survival to ICI increased with higher TMB. Median OS was 42 and 15 months for TMB-H and TMB-L (P &lt; 0.05), respectively. For TMB-H tumors, 5 genes ( STK11, KEAP1, CIC, E2F3, TP53) exhibited reduced OS on ICI, and 22 genes ( NTRK3, TERT, NOTCH3, RNF43, TET1, PTPRD, NCOA3, TENT5C, ZFHX3, RIT1, CCNE1, PPM1D, GATA2, ALK, DNMT1, PTPRT, MET, EPHA7, BCL6, SMO, CDK6, MED12) were associated with better OS, P &lt; 0.05. Cox multivariate analysis confirmed a correlation between mutations in STK11 and E2F3 with worse OS, while mutations in NTRK, PTPRD, RNF43, TENT5C, TET1, and ZFHX3 were associated with better OS (P &lt; 0.05). Histology did not play a relevant role in ICI response except for melanoma (better OS; P &lt; 0.05). MSI status did not significantly affect OS. For TMB-L tumors, 20 genes were related with reduced OS ( TP53, H3C2, DAXX, SMARC4, STK11, SOX17, RB1, PIK3CA, CTNNB1, KMT2D, HLA-A, FBXW7, CDH1, RBM10, KEAP1, IGF1R, H3C11, EGFR, RUNX1, B2M), while 8 genes were associated with better OS ( VHL, SETD2, PBRM1, BRAF, KDM5C, MAP2K1, CSF1R, RET), P &lt; 0.05. Cox multivariate analysis confirmed 15 genes associated with superior ( KDM5C, PBRM1, and VHL) and inferior ( CTNNB1, DAXX, FBXW7, H3C2, H3C1, IGF1R, KMT2D, PIK3CA , RB1, SMARC4, SOX17, TP53) OS (P &lt; 0.05). In the TMB-L context, melanoma histology and MSI status (except among VHL-mutated tumors) were independently associated with better OS. Conclusions: This pan-cancer analysis demonstrates that genomic alterations in single cancer genes can help define outcomes of TMB-H and TMB-L patients treated with ICI. [Table: see text]
Immune landscape of breast tumors with low and intermediate estrogen receptor (ER) expression.
Authors: Leonie Voorwerk, Hugo M. Horlings, Joyce Sanders, Milou S. Keusters, Sten Cornelissen, Gabe S. Sonke, Sabine C. Linn, Marleen Kok
Journal: Journal of Clinical Oncology (2022)

566 Background: Immune checkpoint blockade (ICB) is currently only approved for patients with triple-negative breast cancer (TNBC). However, the cut-off used for ER expression (&lt;1% and in some countries &lt;10%) has been developed as a biomarker for endocrine treatment response and not for selection for likelihood of response to ICB. While stromal tumor-infiltrating lymphocytes (sTILs) and PD-L1 expression are higher in TNBC compared to ER-positive tumors, the distribution of these and other key immune parameters in tumors with very low (1-9%), low (10-50%), intermediate (51-99%) and high (100%) ER levels is unknown. Methods: We collected a consecutive series of treatment-naïve tumor blocks of ER+/HER2- breast tumors diagnosed between 2010 and 2019. All available tumor blocks were used from the groups with ER expression between 1-9% and 10-50%. For the other groups, we randomly selected tumor blocks aiming for similar group sizes. This resulted in the following subgroups: ER 0% (n=46), 1-9% (n=17), 10-50% (n=22), 51-99% (n=37) and 100% (n=51). sTILs were scored using H&amp;E slides. Immunohistochemistry was performed for CD8 and PD-L1 (22C3, scored on immune cells, cut-off ≥1%). Gene expression analysis was performed using the NanoString nCounter Breast Cancer 360 panel. Results: We found the highest levels of sTILs and stromal CD8+ cells in tumors with ER0% with comparable levels in tumors with ER1-9% and ER10-50% (Table). The proportion of PD-L1 positive tumors was 86% in tumors with ER0%, 81% in tumors with ER1-9%, 76% in tumors with ER 10-50% and 59% and 50% in tumors with ER51-99% and 100% respectively. As expected, a higher differentiation grade correlated with lower levels of ER expression. Differential gene expression demonstrated that expression of immune-related signatures, such as IDO1, antigen presenting machinery, CD8+ T cells and IFNγ, was comparable in tumors with ER1-50% as compared to ER0%, but statistically significantly higher as compared to tumors with ER100%. Conclusions: Our data suggest that breast tumors with low levels of ER expression (1-9%, 10-50%) comprise a separate entity within ER-positive breast cancer regarding their immune landscape. Here we show that not only tumors with very low ER levels (1-9%) mimic TNBC in terms of immune landscape but also that tumors with low ER levels (10-50%) might be more likely to respond to ICB than tumors with high levels of ER expression. [Table: see text]
Sex-specific cell types and molecular pathways drive fibro-calcific aortic valve stenosis
Authors: V Myasoedova, I Massaiu, D Moschetta, M Chiesa, V Valerio, M Bozzi, V Parisi, P Poggio
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Fondazione Gigi e Pupa Ferrari ONLUS Background Aortic stenosis (AS) is the most common valve disorder characterized by fibro-calcific remodeling of valve leaflets. Recent evidence indicated that there is a sex-related difference in AS development and progression. Fibrotic remodeling is peculiar of women's aortic valve, while men's aortic leaflets are more calcified than in women. Purpose To assess aortic valve fibrosis (AVF) in a severe AS cohort using non-invasive diagnostic tools and determine whether sex-specific pathological pathways and cell types are associated with severe AS. Methods We have included 28 men and 28 women matched for age with severe AS who underwent Doppler echocardiography and cardiac contrast-enhanced computed tomography (CT) before intervention. The calcium and fibrosis volumes were assessed and quantified using the ImageJ thresholding method, indexed calcium and fibrosis volume were calculated by dividing the volume by the aortic annular area. Differentially expressed genes and functional inferences between women and men's aortic valves were carried out on a publicly available microarray-based gene expression dataset (GSE102249). Cell types enrichment analysis in stenotic aortic valve tissues was used to reconstruct the sex-specific cellular composition of stenotic aortic valves. Results We confirmed that women had significantly lower aortic valve calcium content compared to men, while fibrotic tissue composition was significantly higher in women than men. We identified that the expression profile of human stenotic aortic valves is sex-dependent. Pro-fibrotic processes were prevalent in women, while pro-inflammatory ones, linked to the immune response system, were enhanced in men. Cell-type enrichment analysis showed that mesenchymal cells were over-represented in AS valves of women, whereas signatures for monocytes, macrophages, T and B cells were enriched men ones. Conclusions Our data provide the basis that the fibro-calcific process of the aortic valve is sex-specific, both at gene expression and cell type level. The quantification of aortic valve fibrosis by CT could make it possible to perform population-based studies and non-invasive assessment of novel therapies to reduce or halt sex-related calcific aortic valve stenosis (CAVS) progression, acting in an optimal window of opportunity early in the course of the disease.
Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials
Authors: Silvio Danese, Séverine Vermeire, Wen Zhou, Aileen L Pangan, Jesse Siffledeen, Susan Greenbloom, Xavier Hébuterne, Geert D'Haens, Hiroshi Nakase, Julian Panés, Peter D R Higgins, Pascal Juillerat, James O Lindsay, Edward V Loftus, William J Sandborn, Walter Reinisch, Min-Hu Chen, Yuri Sanchez Gonzalez, Bidan Huang, Wangang Xie, John Liu, Michael A Weinreich, Remo Panaccione
Journal: The Lancet (2022)